title: The RhoGEF TEM4 Regulates Endothelial Cell Migration by Suppressing Actomyosin Contractility.
abstract: Persistent cellular migration requires efficient protrusion of the front of the cell, the leading edge where the actin cytoskeleton and cell-substrate adhesions undergo constant rearrangement. Rho family GTPases are essential regulators of the actin cytoskeleton and cell adhesion dynamics. Here, we examined the role of the RhoGEF TEM4, an activator of Rho family GTPases, in regulating cellular migration of endothelial cells. We found that TEM4 promotes the persistence of cellular migration by regulating the architecture of actin stress fibers and cell-substrate adhesions in protruding membranes. Furthermore, we determined that TEM4 regulates cellular migration by signaling to RhoC as suppression of RhoC expression recapitulated the loss-of-TEM4 phenotypes, and RhoC activation was impaired in TEM4-depleted cells. Finally, we showed that TEM4 and RhoC antagonize myosin II-dependent cellular contractility and the suppression of myosin II activity rescued the persistence of cellular migration of TEM4-depleted cells. Our data implicate TEM4 as an essential regulator of the actin cytoskeleton that ensures proper membrane protrusion at the leading edge of migrating cells and efficient cellular migration via suppression of actomyosin contractility.
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, United States of America ; Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Natalia
authors.initials: N
authors.lastname: Mitin
authors.forename: Kent L
authors.initials: KL
authors.lastname: Rossman
authors.forename: Rachel
authors.initials: R
authors.lastname: Currin
authors.forename: Sandeep
authors.initials: S
authors.lastname: Anne
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Marshall
authors.forename: James E
authors.initials: JE
authors.lastname: Bear
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Bautch
authors.forename: Channing J
authors.initials: CJ
authors.lastname: Der
mesh_terms: D000205:Actomyosin / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology* / Q000378:metabolism; D022001:Focal Adhesions; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D018919:Neovascularization, Physiologic / Q000502:physiology; D064067:Rho Guanine Nucleotide Exchange Factors / Q000502:physiology*
chemical_list: C577226:ARHGEF17 protein, human; D064067:Rho Guanine Nucleotide Exchange Factors; D000205:Actomyosin